Composites of hydroxyapatite and calcium carbonate and related methods of preparation and use

ABSTRACT

Carbonated calcium phosphate compositions and methods of preparation, affording enhanced biophysical properties.

This application claims priority benefit from application Ser. No.61/406,725 filed Oct. 26, 2010, the entirety of which is incorporatedherein by reference.

BACKGROUND OF THE INVENTION

Hydroxyapatite (HA) is considered to be one of the best, if not the bestscaffolds for bone growth. However, it is slow to resorb (and has lowwater solubility), and for that reason there is much interest inalternative materials that resorb faster than HA but still provide goodbiological properties. One approach is to use alternative calciumphosphates that dissolve more rapidly, such alternative materialsincluding TCP, or mixtures of HA and TCP (biphasic). Another approachthat can be used alone or combined with other chemistries is to altermaterial physical structure to increase the surface area—such as byintroducing porosity, and/or by lowering the sintering temperature toreduce density.

Yet other approaches use non-calcium phosphate materials such as calciumsulfate or calcium carbonate. Carbonate-substituted HA is normally foundin nature, and the carbonate can replace some of the hydroxide on thecalcium hydroxide component and/or substitute some of the phosphategroups with carbonate. This material is very biologically compatible,but is available only as powder because it cannot be sintered to a highdensity, as sintering above about 825 degrees transforms the carbonategroups to oxide groups. Accordingly, HA and calcium carbonate have beenused together as layered materials. One such commercial material has anouter, hydrothermally formed HA layer on a calcium carbonate core. Anoperative theory is that the HA outer layer provides initial stabilityand accelerated bone bonding in the graft site, while the calciumcarbonate core ensures rapid remodeling once the thin outer layer of HAgoes away. Alternatively, calcium sulfate can be used alone as a bonegrafting material. However, it is not as osteoconductive as calciumphosphate materials, and—unlike HA—tends to resorb too quickly in manysituations. Calcium carbonate can also be used alone as a bone graftingmaterial, but it has many of the disadvantages of calcium sulfateincluding excessively rapid dissolution.

SUMMARY OF THE INVENTION

In light of the foregoing, it is an object of the present invention toprovide various calcium phosphate-related compositions, compositesand/or method(s) for their preparation, thereby overcoming variousdeficiencies and shortcomings of the prior art, including those outlinedabove. It will be understood by those skilled in the art that one ormore aspects of this invention can meet certain objectives, while one ormore aspects can meet certain other objectives. Each objective may notapply equally, in all its respects, to every aspect of this invention.As such, the following objects can be viewed in the alternative withrespect to any one aspect of this invention.

It can be an object of the present invention to provide variouscarbonated hydroxyapatite materials compositionally distinct from andheretofore unavailable in the art.

It can also be an object of the present invention to provide such abiocompatible composite/composition with steady remodeling rates, suchrates as enhanced by comparison to the prior art.

It can also be an object of the present invention, regardless of anyparticular composite/composition, to provide a method of preparationsuch that a resulting material can be sintered without carbonate loss.

It can also be an object of the present invention, alone or inconjunction with one or more of the preceding objectives, to providedense, non-powder, granular materials useful in a variety of end-useapplications, including bone grafting.

Other objects, features, benefits and advantages of the presentinvention will be apparent from the summary and the followingdescriptions of certain embodiments, and will be readily apparent tothose skilled in the art having knowledge of various biocompatiblehydroxyapatite compositions and techniques for their preparation. Suchobjects, features, benefits and advantages will be apparent from theabove as taken into conjunction with the accompanying examples, data,figures and all reasonable inferences to be drawn therefrom, alone orwith consideration of the references incorporated herein.

In part, the present invention can be directed to a compositioncomprising a two-phase composite comprising a matrix phase comprising asintered calcium phosphate component and a discontinuous phase withinsuch a matrix phase, such a discontinuous phase comprising a pluralityof elongated carbonate inclusions. In certain embodiments, such acalcium phosphate component can be selected from sintered hydroxyapatitematerials with a Ca/P ratio equal to about or greater than about 1.67.In certain such embodiments, an amount of excess calcium, equal to about10% to about 25% or more of the total amount of calcium contained in thehydroxyapatite phase can be calcium carbonate. Alternatively, in certainsuch embodiments, about 15% to about 20% of such a composition can becalcium carbonate. The remainder of any excess calcium not calciumcarbonate can be in the form of a non-carbonate salt of calcium such asbut not limited to calcium oxide, calcium hydroxide, or a calcium saltother than calcium carbonate.

Regardless, such a composition can have a non-powder, granulatemorphology—whether porous or non-porous. In certain such porousembodiments, a pore of such a composition can have a cross-dimension ofabout 50 microns to about 2000 microns. In certain such embodiments,such a cross-dimension can be about 200 microns to about 600 microns.

In part, the present invention can also be directed to a two-phasecomposite comprising a hydroxyapatite matrix phase and a discontinuousphase within such a matrix phase, such a composite comprising a Ca/Pratio greater than about 1.67 and such a discontinuous phase comprisinga plurality of elongated inclusions comprising a at least a portion ofsuch excess calcium. In certain embodiments, such inclusions of such adiscontinuous phase can comprise about 15% to about 20% or more of anysuch excess calcium component.

Regardless, such inclusions can have a length dimension of about 5microns to about 20 microns. Without limitation, at least about 90% ofsuch inclusions can have a cross-dimension of less than about 10microns. Without limitation as to either inclusion length orcross-dimension, such a composite—whether porous or non-porous—can besintered and/or have a non-powder, granulated morphology.

In part, the present invention can also be directed to a method ofpreparing a two-phase carbonated hydroxyapatite composition. Such amethod can comprise providing a hydroxyapatite material comprising acarbonatable calcium component, such a calcium component providing sucha hydroxyapatite material a Ca/P ratio equal to about or greater thanabout 1.67; sintering such a hydroxyapatite material; and treating sucha sintered hydroxyapatite material with a carbon dioxide source toconvert at least a portion of such a calcium component thereof to adiscontinuous calcium carbonate phase within such a hydroxyapatitephase. In certain embodiments, such a Ca/P ratio can be about 1.67. Incertain other embodiments, such a Ca/P ratio can be greater than about1.67, and such a hydroxyapatite material can comprise an extraneouscarbonatable calcium component. Without limitation, such an extraneouscomponent can be selected from calcium oxide, and a calcium oxideprecursor selected from calcium hydroxide, calcium carbonate, calciumnitrate, calcium sulfate and calcium salts of organic acids andcombinations of calcium oxide and/or calcium oxide precursors.

Without limitation, such a hydroxyapatite material can be sintered at atemperature up to about 1200° C. Optionally, such a material can bepartially or less than fully sintered. In certain such embodiments, lesssintering can provide more carbonate conversion. Regardless of theextent of sintering, such a carbon dioxide source can be provided in afluid form. In certain such embodiments, without limitation, such afluid form can be selected from gaseous and liquid states of carbondioxide and solutions comprising such a gaseous or liquid state.

In part, the present invention can also be directed to a compositioncomprising a two-phase calcium phosphate composite characterized by anX-ray diffraction pattern comprising major peaks expressed in degreestwo-theta at about 29.5°, about 36.0°, about 39.5°, about 43.0° andabout 57.5°, such a composite obtainable by or as be produced by aprocess comprising sintering a hydroxyapatite material comprising acarbonatable calcium component and carbonating such a sintered material,such a composite comprising the carbonation product of such a calciumcomponent as elongated crystalline inclusions therein.

In certain embodiments, such a composition can have a porous granulatedmorphology. Without limitation, a pore can have a cross-dimension ofabout 50 microns to about 2000 microns. In certain such embodiments, apore can have a cross-dimension of about 200 microns to about 600microns. Regardless, as can be used to distinguish this and variousother embodiments of this invention from powders of the prior art, suchgranules can have a cross-sectional dimension greater than about 100microns.

In part, the present invention can also be directed to a method of usingelongated carbonate inclusions to affect the strength of ahydroxyapatite material. Such a method can comprise providing a sinteredhydroxyapatite material comprising a carbonatable calcium component,with such a component providing such a material a Ca/P ratio equal toabout or greater than about 1.67; and contacting such a sinteredhydroxyapatite material and a carbon dioxide source, such contact atleast partially sufficient to provide elongated carbonate inclusionswithin such a hydroxyapatite material. As demonstrated herein, suchinclusions can affect and/or enhance the strength of such a carbonatedhydroxyapatite material versus the strength of an uncarbonatedhydroxyapatite material. In certain embodiments, such a carbonatedhydroxyapatite material can be sintered at a temperature of about 800°C. Regardless, strength affected by such a method can be gauged by crushtest compression and/or particle size data.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-C provide x-ray diffraction spectra on pre- and post-conversionhydroxyapatite, with comparison to calcium oxide and calcium carbonatestandards.

FIGS. 2A-C provide x-ray diffraction spectra for post-conversionhydroxyapatite compositions, in accordance with various non-limitingembodiments of this invention.

FIGS. 3A-B and 4A-B provide, respectively, scanning electron micrographimages of hydroxyapatite and a non-limiting carbonated hydroxyapatitecomposite.

FIGS. 5A-C graphically represent comparative performance test results ofan uncarbonated hydroxyapatite sample and representative carbonatedhydroxyapatite composites of this invention.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

With respect to certain non-limiting embodiments, this invention can beconsidered in the context of a molecular mixture of HA and calciumcarbonate. Calcium phosphate and calcium carbonate particles are formedin situ from excess calcium species incorporated into an HA material,producing in an intimate mixture of HA and calcium carbonate that cannotbe achieved by mere physical mixing of the two materials. The resultingcrystallite size is such that the x-ray diffraction (XRD) pattern showsa crystal pattern for each, and each phase is observable undersufficient magnification, but there is no way to physically separate thecomponent phases. Mixing on this level ensures much greater uniformitythan can be obtained through a physical mixing process.

One such HA material of this invention is carbonated after sintering.Only the calcium hydroxide groups are converted (there is no phosphategroup substitution), but this still provides many of the chemicalfeatures of natural carbonated HA with the added advantage that it canbe in a physical form other than powder. For example, it can be madeinto a porous granulate material (e.g., a particle cross-sectiondimension greater than about 100 microns) which is very useful in bonegrafting applications. (For reference purposes, HA, as compared totricalcium phosphate (TCP), contains extra calcium in the form ofcalcium hydroxide to provide a Ca/P ratio of 5/3 (1.67) versus the 3/2Ca/P ratio of TCP; formula of HA: Ca₉(PO₄)₆Ca(OH)₂, formula of TCP:Ca₉(PO₄)₆.)

Another embodiment is a material where the amount of calcium in the HAis increased above the Ca/P ratio of HA (i.e., greater than 5/3 or1.67), and substantially all of the excess calcium is in the form ofcalcium carbonate. The calcium associated with the HA (within the 5/3Ca/P ratio) may or may not be in the form of calcium carbonate.Advantages are that the excellent bone biocompatibility of HA isretained, but the remodeling rate is increased due to the presence ofthe calcium carbonate. Unlike multiple layered materials of the priorart (for example a calcium carbonate material where the outer layer istransformed to HA), the remodeling rate of such a material of thisinvention is roughly constant because the carbonate is evenly dispersedthroughout, which makes for greater predictability. Furthermore, becausethe material can be fully sintered, it is stronger than many of thelower density (less than fully sintered) forms of HA that are made in anattempt to decrease the remodeling time of HA.

The present invention is not a mere physical mixture of HA and calciumcarbonate, as evidenced by an apparent limit as to how much carbonatecan be incorporated into such a material. With a physical mixture, therewould be no upper limit of carbonate incorporation. However, withrespect to certain non-limiting embodiments, about 10% to about 25% ofany excess calcium oxide (or another suitable carbonate precursor),representing calcium in excess of a Ca/P ratio of 1.67, can be convertedto carbonate. At higher oxide levels, conversion to carbonate may not becomplete. Among other related observations, the less an initialHA/calcium oxide/precursor material is sintered the higher the amount ofcarbonate conversion. Without limitation as to any one theory or mode ofoperation, carbonate anions are physically larger than oxide ions andhave a corresponding spatial requirement within a crystal lattice. It isbelieved that less sintering correlates to lower material density, andlower density provides more space for physically larger carbonateanions. All such considerations provide further evidence that thisinvention is not a mere physical mixture but that calcium carbonate iscrystallized within and/or incorporated into an HA lattice.

Neutralization of Excess Calcium Oxide or Hydroxide in the Material.

If the conversion to calcium carbonate is not complete and some calciumoxide or hydroxide is left it may be desirable to convert some or all ofthe excess calcium oxide or hydroxide to a calcium salt. This can bedone by reacting an acid (preferably an approximately stoichiometricamount of acid relative to the calcium hydroxide or calcium oxide) withthe material. The reaction can be carried out in a water solution, or inthe case of a volatile acid such as HCl, the acid can be in the vaporphase to react with the solid calcium oxide or calcium hydroxidecontaining material.

Description of Calcium Carbonate Materials and Processes.

A process/method of this invention can begin with a material which ismade by producing sintered HA with an excess of calcium oxide (or amaterial capable of being transformed to calcium carbonate such ascalcium hydroxide), where the calcium phase (either intrinsic to the HAor additional calcium material, or both) is converted to carbonate by,for example, exposure to CO₂ in some form such as a gas, a watersolution (carbonic acid) a supercritical fluid, or a compound capable oftransferring carbon dioxide. More generally, such a calcium phase can,in the context of this invention, be considered a carbonatable calciumcomponent, capable of being converted to calcium carbonate—suchconversion as would be understood by those skilled in the art throughuse of known techniques, reaction conditions and reagents, including butnot limited to those discussed herein.

The process of calcium carbonate formation is generally carried out onsintered HA. Normally, the high temperatures of sintering (if carriedout in an oxygen containing atmosphere) transforms most calciumcompounds to calcium oxide. Examples of compounds that can betransformed to calcium oxide by heating in an oxygen containingatmosphere are: calcium hydroxide, calcium carbonate, calcium nitrate,calcium sulfate; and calcium salts of organic acids. To facilitate thereaction with carbon dioxide, the calcium oxide can be transformed tocalcium hydroxide by exposure to water or water vapor, for example,boiling the material in water.

Producing a Precursor Material.

A preferred process involves addition of extra calcium (for example,calcium oxide or a calcium oxide precursor) to the HA before sintering.The calcium compound can be added to unsintered HA, mixed in by anysuitable means, and then the mixture can be sintered. Preferably, thematerials to be mixed are powders, and they may be mixed by any suitablemeans including a grinding/mixing procedure such as ball milling. It isalso possible to use a liquid such as water, alcohol, hexane, etc. tofacilitate the mixing process. As shown by comparison to the prior art,it is not possible to obtain a molecular mixture of HA and calciumcarbonate solely by physical mixing, even if calcium carbonate is usedas the calcium compound. Neither calcium carbonate nor HA are completelysoluble in any solvent except an acid solution, so (with the exceptionof an acid solution), at best, the end material is a mixture ofparticles, and is not mixed at the molecular level. Further, in an acidsolution (except for carbonic acid), carbonate decomposes to carbondioxide gas and calcium hydroxide. However, the process of sinteringfacilitates the intermingling of the calcium oxide/hydroxide and thecalcium phosphate materials to provide more intimate mixing than can beachieved by physical mixing alone. If an acid solution is used (beforeor in place of sintering), the chemistry is altered, and the materialupon drying no longer contains just calcium oxide/carbonate and HA. Oneuseful embodiment of this is to use carbonic acid as the acid source. Anapproximately stoichiometric amount of carbonic acid can be used to formthe carbonated material directly without changing other aspects of thechemistry.

An especially convenient method of making a precursor material is toreact phosphoric acid with an excess of calcium hydroxide. One of thecommon commercial methods of making HA is by reacting phosphoric acidwith calcium hydroxide; accordingly, in certain embodiments, thisinvention can represent a methodology including an excess of calciumhydroxide in the reaction mixture.

Formation of Calcium Carbonate In-Situ.

During sintering, the added calcium precursor remains mixed at themolecular level with the HA, and remains in place during cooling.Preferably, the sintering will be carried out at a temperaturesufficient to convert such a calcium compound to calcium oxide. The mostdirect way to convert the calcium oxide to calcium carbonate in thesintered mixture is to, at a temperature below the approximately 825° C.decomposition temperature of calcium carbonate, expose the sinteredmaterial to CO₂ gas (either pure or in a gas mixture such as air,nitrogen, water vapor, etc.) until the desired conversion of the calciumoxide to calcium carbonate is achieved. The advantage of this method, asopposed to sintering a reaction mixture containing calcium carbonate andcalcium phosphate, is that much higher sintering temperatures can beused, which will result in a stronger, denser material. Hydroxyapatitecontaining excess calcium, for example, can be sintered at up to about1200° C., and the excess calcium can then be converted to the carbonateform post sintering; while a calcium carbonate/calcium phosphate mixturecan only be sintered to a temperature of about 800° C. while retainingthe carbonate phase.

In carrying out the conversion of the sintered material to carbonate,the concentration of CO₂ in the treatment gas can be as little as 0.001%or as high as 100%. The CO₂ concentration mainly affects the rate ofconversion, with higher CO₂ concentrations giving a faster conversion.The reaction with carbon dioxide gas can be facilitated by suspendingthe calcium oxide containing calcium phosphate in water. Another way tofacilitate the reaction is to transform the calcium oxide to calciumhydroxide by, for example, boiling the calcium oxide containing materialin water, then (optionally) drying it. Solid calcium hydroxide reactsfaster with carbon dioxide than solid calcium oxide. Heat can also beused to facilitate the reaction. The temperature should be below thedecomposition point of calcium carbonate (which is about 825° C.).Temperatures can be above or below the decomposition point of theprecursor material as long as the temperature is below the decompositiontemperature of calcium carbonate; for example calcium hydroxide melts atabout 580° C. and decomposes at a somewhat higher temperature. This isstill below the 825° C. decomposition temperature of calcium carbonate.A reaction carried out at a temperature above the melting point ofcalcium hydroxide may be useful in providing a denser material than ifthe reaction were carried out below the melting point.

Water can be used to facilitate the reaction by immersing the solidmaterial to be treated in water, then bubbling the CO₂ through thewater. While some of the calcium content of the solid material maydissolve in the water and be lost, some will also remain with the solidin a converted form as long as the reaction is not run too long. Afterthe reaction is completed, the solid can be separated from the water bycentrifugation, filtration, decantation, etc. In addition to using CO₂gas for carbonate conversion, the CO₂ can be in a liquid form, includingthe form of a supercritical fluid, or a chemical solution capable ofcausing the conversion (such as carbonic acid, etc.).

The degree of sintering can affect the conversion. Fully sintering thematerial to a very dense material can make the conversion moredifficult: as a molecular mixture, a dense crystal lattice can beconsidered as having less room for the larger carbonate ions (or evenfor the hydroxide ions in place of calcium oxide). Therefore, dependingon the amount of carbonate desired, it may be necessary to lower thesintering temperature to achieve the full conversion. Alternatively, thelattice density can be decreased by introducing ions known to reduce thedensity of HA such as magnesium, zinc, manganese, etc.

It is preferred that the mixed material be sintered before the carbonateconversion is carried out, but it is also possible to obtain a molecularmixture without sintering. This can be done, for example, by reactingphosphoric acid with excess calcium oxide or calcium hydroxide (suchthat a molecular mixture is formed as the phosphoric acid isneutralized), then drying the mixture, and reacting it with carbondioxide to achieve the conversion to calcium carbonate.

If calcium carbonate is added directly to the phosphoric acid, mostlikely a post drying CO₂ treatment will still be needed because the acidconditions liberate carbon dioxide from calcium carbonate and transformit into the hydroxide. But, if the amount of phosphoric acid is notenough to neutralize all of the calcium carbonate (the final Ca/P ratiois over 3/2) there will be calcium carbonate remaining in the mixturewhich could be sufficient by itself.

With respect to the present invention, the methods, composites,compositions and/or phases thereof can suitably comprise, consist of orconsist essentially of any of the aforementioned components, materialsor compounds. Each such component, material and/or compound iscompositionally distinguishable, characteristically contrasted and canbe practiced in conjunction with the present invention separate andapart from another. Accordingly, it should also be understood that theinventive compositions, composites and/or methods, as illustrativelydisclosed herein, can be practiced or utilized in the absence of any onecomponent, material and/or compound which may or may not be disclosed,referenced or inferred herein, the absence of which may or may not bespecifically disclosed, referenced or inferred herein. Likewise, itshould be understood that the inventive compositions, composites and/ormethods of this invention can be expressed or claimed providing for anyone or more specific components, materials, compounds and/or steps, orby reciting the absence of any one or more specific components,materials, compounds and/or steps.

Whether or not expressly indicated, all numbers expressing component,material and/or compound quantities, concentrations or proportions(e.g., ratios and factors of ratios), dimensions, properties, reactionor process parameters or conditions, and so forth used in thespecification and claims are to be understood as being modified in allinstances by the term “about”. Accordingly, unless indicated to thecontrary, the numerical values set forth in the specification and theattached claims are approximations that may vary depending upon thedesired properties sought to be obtained by the present invention. Atthe very least, and not as a limitation of application of the doctrineof equivalents to the scope of such claims, each numerical value shouldbe construed in light of the number of reported significant digits andby applying ordinary rounding techniques.

EXAMPLES OF THE INVENTION

The following non-limiting examples and data illustrate various aspectsand features relating to the compositions, composites and/or methods ofthe present invention, including the preparation of carbonatedhydroxyapatite materials, as are available through the syntheticmethodologies described herein. In comparison with the prior art, thepresent methods and compositions/composites provide results and datawhich are surprising, unexpected and contrary thereto. While the utilityof this invention is illustrated through the use of several calciumphosphate compositions/composites and hydroxyapatite and carbonatecomponents thereof, it will be understood by those skilled in the artthat comparable results are obtainable with various othercompositions/composites and components thereof, as are commensurate withthe scope of this invention.

Example 1

Calcium hydroxide (4120 grams) was suspended in 40 liters of water in a30-gallon plastic tank under continuous agitation. Phosphoric acid, 85%concentration, (3110 grams) was slowly added to the calcium hydroxide.This resulted in about a 21% excess of calcium hydroxide over thatneeded to make hydroxyapatite. After 24 hours, the reaction mixture wasconcentrated in a filter press. The filter cake was collected and driedin an oven at 120° C. The dried material was broken into random sizedlumps and transferred to alumina crucibles, then sintered at 1100° C.for 4 hours (with an 8-hour heating ramp). After cooling, the sinteredmaterial was checked by x-ray diffraction and found to contain about 79%HA and 21% calcium oxide.

Example 2

Some of the material (10 grams) from Example 1 was boiled in (300 ml)water for 3 hours to transform the calcium oxide to calcium hydroxide.The ratio of solids to water was about 1:30. XRD analysis of a sampleconfirmed the conversion of the calcium oxide to calcium hydroxide.

Example 3

About 50 grams of the boiled material from Example 2 was transferred toboat crucibles and put into a tube furnace. The ends of the tube furnacewere sealed except for a ¼ inch hole at the back end and a ¼ inch inletpipe in the front end. A flow of about 6 cubic ft./hour of CO₂ was fedinto the furnace through the tube and the furnace was held at 500° C.for 12 hours. XRD analysis of the treated material showed that all ofthe calcium oxide had transformed to calcium carbonate, while the HA wasunchanged.

Example 4

About 10 grams of material from Example 1 was put in a 250 ml gasbubbler jar. It was covered with about 75 ml of water, and stirred witha magnetic stirring bar while CO₂ was bubbled through at a rate of about1 standard cubic foot per hour (SCFH). The reaction ran for 2 hours. ThepH was initially about 8.5. At the completion of the reaction the pH wasabout 6.0. The material was separated from the water by centrifugation,then dried at 90° for 4 hours. XRD analysis showed that the calciumoxide content decreased from 21% to 5%, and the carbonate content was8%. The supernatant water solution, which was cloudy, was dried and theresulting solid was analyzed by XRD. It was found to be HA with a highproportion of calcium carbonate (about 25%). It was concluded that theconversion reaction converted about half of the calcium oxide in place,but that fragments of the original material broke off during the process(probably from contact with the stirring bar) and became more highlycarbonated. Some carbonate may have dissolved during the CO₂ treatmentand precipitated on carbonated HA powder during the drying process.

Example 5

Calcium hydroxide (4120 grams) was suspended in 40 liters of water in a30-gallon plastic tank under continuous agitation. Phosphoric acid, 85%concentration, (3110 grams) was slowly added to the calcium hydroxide.This resulted in about a 21% excess of calcium hydroxide over thatneeded to make hydroxyapatite. After 24 hours, the reaction mixture wasconcentrated in a filter press. The filter cake was collected and driedtransferred to drying pans. The material was placed in a vacuum oven,the air was evacuated, and the oven was backfilled with carbon dioxideand the temperature was raised to 30 degrees C. The material was left inthe carbon dioxide atmosphere for 18 hours, then removed and transferredto alumna crucibles. The material was sintered at 800 degrees, and uponXRD analysis it was found that the excess calcium had fully converted tocalcium carbonate. The lower sintering temperature is believed to haveprevented thermal decomposition of the carbonate material.

Example 6

In accordance with certain non-limiting embodiments of this invention,porous composites and/or compositions can be prepared using techniquesknown in the art.

Example 6a

A slurry containing calcium phosphate is produced having a molar ratioof calcium to phosphate greater than 1.67. The pH of the calciumphosphate slurry is then reduced to an ideal range of 7 to 4. It can bereduced by adding a buffer or acid; or preferably by converting thecalcium oxide (or calcium hydroxide) present in the material tocarbonate exposure to carbon dioxide gas. A carbomer and/or polyethyleneglycol is then added to the slurry, and allowed to mix for greater thanone hour. Once sufficient mixing has taken place hydrogen peroxide isadded to the mixture. At this point the mixture can be placed in aheated oven and allowed to dry. Once dry, the material is sintered at atemperature greater than 600 C, but preferably less than 1200 C. Thematerial is then placed in water or a water atmosphere to convert anyCaO present to CaOH. Once the CaO is converted the material is placed ina CO₂ atmosphere until the desired amount of carbonation is achieved.(If the material is converted to the carbonate form before sintering,and is sintered to a temperature below about 800 C, then the aftersintering carbonate conversion step is not necessary.)

Example 6b

A slurry containing calcium phosphate is produced having a molar ratioof calcium to phosphate greater than 1.67. The mixture is thendehydrated to a powder, ideally using a spray dryer. The powder is thenmixed with a pore-making material until a homogenous mixture isachieved. (The pore-making material can be an organic material thatburns away completely during sintering leaving holes (pores) in itsplace. Examples include polymer fibers, or even thin (dry) spaghettirods.) The calcium phosphate/porogen mixture is then pressed to itsdesired shape at a pressure greater than 1000 psi, but ideally greaterthan 5000 psi. The pressed piece is than is sintered at a temperaturegreater than 600 C, but preferably less than 1200 C. Sintering should bedone so that the pore making material completely burns out of thematerial. The material is then placed in water or a water atmosphere toconvert any CaO present to CaOH. Once the CaO is converted the materialis placed in a CO₂ atmosphere until the desired amount of carbonation isachieved.

Example 6c

A slurry containing calcium phosphate is produced to having a molarratio of calcium to phosphate greater than 1.67. The mixture is thanthickened so that the slurry sticks to a polyethylene sponge while stillpreserving its pores. The sponge is then dried in a heated oven. Oncedry the sponge is sintered to greater than 600 C, but preferably lessthan 1200 C. Sintering should be done so that the sponge completelyburns out. The material is then placed in water or a water atmosphere toconvert any CaO present to CaOH. Once the CaO is converted the materialis placed in a CO₂ atmosphere until the desired amount of carbonation isachieved.

Example 6d

Whether or not porous, granulated composites and/or compositions of thisinvention can be prepared by appropriate grinding and sieving. Forinstance, porous materials prepared as described in examples 6a-c can beground to a non-powder granulate of particle cross-dimension greaterthan about 100 microns.

Example 7

X-ray diffraction (XRD) studies were undertaken on pre- andpost-conversion HA, with scans of calcium oxide and calcium carbonatestandards provided for purpose of comparison. FIG. 1 provides an XRDpattern for pre-conversion HA. FIG. 1B provides, for comparisonpurposes, an XRD pattern for calcium oxide. FIG. 1C provides acomparative XRD pattern for calcium carbonate, showing post-conversioncarbonate peak positions (*) not present in pre-conversion HA(comparative reference is made to FIG. 1A).

FIG. 2A provides an XRD pattern for post-conversion HA and shows, forcomparison, calcium oxide peak positions. FIG. 2B provides an XRDpattern for post-conversion HA and shows, for comparison, peak positionsfor pre-conversion HA. FIG. 2C provides an XRD pattern forpost-conversion HA and shows, for comparison, peak positionsattributable to carbonate conversion.

Example 8

Two sets of scanning electron micrograph (SEM) images of HA andcarbonated HA are provided, respectively, in FIGS. 3A-B and 4A-B.Reference is made to the elongated inclusions, in random orientation(FIGS. 3B and 4B, respectively), after carbonation of the initial HAmaterial. (FIGS. 3A and 4B, respectively).

Example 9

The strength of a non-porous carbonated apatite material of thisinvention was tested and compared to non-porous uncarbonated HA using acrush test. The uncarbonated HA sample was sintered at 800° C., and thesame temperature was used to sinter the calcium oxide/HA precursormaterial for the carbonated apatite sample, which was fully converted toa final carbonate content of 15%. Both samples were ground and sieved toa particle size range of 750 to 1000 microns. (It will be understood bythose skilled in the art that porous materials of this invention can beprepared using known synthetic techniques and reagents.)

The crush testing was carried out on a Quantrol by Dillon compressiontest instrument fitted with a 35 pound load cell. The test chamber was a¼ inch diameter cavity, 2.5 inches deep. The sample to be tested was putin the cavity (1 inch of material) followed by a stainless steel rodthat closely fitted the cavity and was used to transmit force from theload cell to the sample. The compression test was carried out at a speedof ⅛ inches/minute, and both force and displacement were measured up toa maximum applied load of 35 pounds.

The uncarbonated HA sample was compressed about 0.09 inches, while thecarbonated HA sample was compressed about 0.03 inches. (See, FIG. 5A,graphic plots 1 and 2, respectively) Sieve analysis of the materialsshowed very significant crushing of the HA sample, but little crushingof the carbonated HA sample. About 76% of the carbonated HA sample wasstill above 710 microns (FIG. 5B), while only about 40% of the HA samplewas still above 710 microns(FIG. 5C). Such data clearly demonstratesthat a carbonate/HA of this invention has composite physical properties,and is not merely a physical mixture of HA and calcium carbonate. Note,also, that standard sintering temperatures range from about 1100°C.-1200° C., and strength and density increases with sinteringtemperature. However, contrary to the prior art, enhanced strength wasobserved here at a much lower sintering temperature (of 800° C.)—therebyavoiding densification of the sort that would otherwise impederesorption.

While the principles of this invention have been described in connectionwith specific embodiments, it should be understood clearly that thesedescriptions are added only by way of example and are not intended tolimit, in any way, the scope of this invention. For instance, thecomposites and/or compositions of this invention can be used as orincorporated into various bone grafting or implant materials and/or usedas an osteoconductive scaffold for promoting bone growth. Otheradvantages and features will become apparent from the claimshereinafter, with the scope of such claims determined by the reasonableequivalents, as understood by those skilled in the art.

I claim:
 1. A two-phase composite comprising a hydroxyapatite matrixphase and a discontinuous phase within said matrix phase, said compositecomprising a Ca/P ratio greater than about 1.67, said discontinuousphase comprising a plurality of elongated, randomly-oriented calciumcarbonate inclusions having a length dimension of about 5 microns toabout 20 microns, said calcium of said inclusions the excess calciumportion of said Ca/P ratio.
 2. The composite of claim 1 wherein at leastabout 90% of said inclusions have a cross-dimension less than about 10microns.
 3. The composite of claim 1, sintered.
 4. The composite ofclaim 3 comprising a granulated morphology.
 5. A composition comprisinga two-phase composite comprising a hydroxyapatite matrix phase and adiscontinuous phase within said matrix phase, said composite comprisinga Ca/P ratio greater than about 1.67, said discontinuous phasecomprising a plurality of elongated calcium carbonate inclusions havinga length dimension of about 5 microns to about 20 microns, said calciumof said inclusions the excess portion of said Ca/P ratio.
 6. Thecomposite of claim 5 comprising a non-powder granulate morphology. 7.The composite of claim 6 comprising granules having a cross-dimensiongreater than about 100 microns.